The overall objective of our research during the previous funding period was to characterize the distribution of expression, structure, and function, of a novel glycoprotein antigen, Mo3, expressed by activated human mononuclear phagocytes. We accomplished these objectives and discovered that the Mo3 glycoprotein represents the cellular receptor for urokinase plasminogen activator (uPA-R) that is not only expressed by activated phagocytes (both macrophages and PMNs) but also many tumor cells of both hematopoietic and nonhematopoietic origin. Since receptor bound uPA is catalytically active (functioning to convert receptor bound plasminogen to the serine protease plasmin) and cellular uPA content has been positively correlated with the invasive potential of inflammatory and neoplastic cells, uPA-R (in conjunction with cellular receptors for plasminogen) may serve to focus the capacity of these cells to degrade extracellular matrix during inflammatory diapedesis and metastatic invasion. Having thus defined the molecular identity of the Mo3 glycoprotein, we now propose to fully test the hypothesis that uPA-R plays a critical role in the invasive behavior of both tumor cells and inflammatory phagocytes and whose function may depend upon an association with other plasma membrane molecules such as the integrin of glycoproteins. The Specific Aims of the proposed research plan are as follows: (I) generate mAb that recognize uPA-R epitopes outside of the ligand binding domain so as to assess the function of other regions of the glycoprotein; (2) assess the functional role of uPA-R oligosaccharides in ligand binding and receptor-mediated signalling events; (3) assess the possibility of a functional association between uPA-R and one or more plasma membrane species that may promote uPA-R-dependent signalling and influence the motility and/or invasive capacity of uPA-R-expressed by phagocytes or tumor cells; (4) assess the extent to which cell-associated or soluble uPA-R (as detected serologically by mAb or polyclonal reagents) represents a clinically useful marker of acute and/or chronic inflammation or a prognostic factor in human cancer (as represented by breast and certain other human malignancies); and (5) generate human breast carcinoma cell line(s) in which uPA-R expression is amplified so as to assess the extent to which amplified uPA-R expression influences the invasive capacity of these transfected cells in vitro and in vivo. The outcome of these experiments should provide new insights about the physiological significance of uPA-R expression by human phagocytic and tumor cells.